Thursday, 17 February 2022 11:54

Un estudio muestra cómo el fármaco plitidepsina inhibe la reproducción del SARS-CoV-2 dentro de las células

  • Actúa sobre las células e impide la formación de los espacios donde se reproduce el virus, según revela un estudio coliderado por investigadoras del CSIC e IrsiCaixa

Un estudio coliderado por investigadores del Consejo Superior de Investigaciones Científicas (CSIC) ha mostrado cómo actúa el fármaco aplidin (plitidepsina) para inhibir la replicación del coronavirus SARS-CoV-2 dentro de las células humanas: el fármaco impide la formación de compartimentos celulares donde se replica el material del virus. De este modo, interfiere en las células y evita la progresión de la infección viral. Su funcionamiento refuerza su potencial para combatir futuras variantes del SARS-CoV-2, pues este paso de la replicación del virus es común a todas las variantes del virus. El estudio, en fase de revisión, se presentó ayer en la Conferencia sobre Retrovirus e Infecciones Oportunistas (CROI), en Barcelona.

El fármaco plitidepsina, comercializada con el nombre de aplidin, ha sido uno de los fármacos que ha demostrado mayor eficacia para bloquear la replicación del SARS-CoV-2 en experimentos de laboratorio. “Cuando pusimos en marcha este estudio para analizar la actividad antiviral de plitidepsina en la célula, no esperábamos descubrir que su diana de actuación se encontraba en un estadio tan inicial de la replicación del SARS-CoV-2”, explica Cristina Risco, investigadora del Centro Nacional de Biotecnología (CNB-CSIC) y co-líder del estudio junto a investigadores del Instituto de Investigación del Sida IrsiCaixa, el Centro de Investigación en Sanidad Animal (IRTA-CReSA) y la farmacéutica PharmaMar.

El fármaco bloquearía una molécula de la célula huésped que es necesaria para que el SARS-CoV-2 pueda formar las vesículas donde se fabrican nuevos virus. A diferencia de la gran mayoría de antivirales, plitidepsina –fármaco que se encuentra en un ensayo clínico de fase III– actúa sobre la célula huésped y no sobre el virus, bloqueando procesos esenciales y compartidos entre las diferentes variantes del SARS-CoV-2. Este hecho la convierte en una potencial herramienta para combatir no sólo el actual SARS-CoV-2, sino futuras variantes que puedan emerger.

Evitar la replicación del SARS-CoV-2 desde el principio

El personal investigador que ha realizado el estudio ha demostrado, en cultivos celulares en el laboratorio, que bajas cantidades de plitidepsina son capaces de inhibir, 48 horas después de la infección por el SARS-CoV-2, la capacidad de replicación del virus. “A través de técnicas de microscopía electrónica, hemos podido ver cómo, en presencia del fármaco, las vesículas de doble membrana, que son los compartimentos celulares en los que se replica el material genético del SARS-CoV-2, no se forman. Pensamos que esto se debe a que las proteínas no estructurales del virus necesarias para la creación de estas vesículas no llegan a formarse como consecuencia de la acción del fármaco”, detalla Martin Sachse, investigador del CNB-CSIC y del Instituto de Salud Carlos III y primer autor del trabajo.

El equipo también ha comprobado la no formación de nuevas partículas virales con técnicas de inmunotinción. “Podemos confirmar que plitidepsina actúa en un punto muy temprano del ciclo de infección viral, concretamente en el momento en que el material genético del SARS-CoV-2 envía órdenes para que se produzcan las proteínas virales que formarán los compartimentos donde los virus replican su material genético y dirigen la síntesis de nuevos virus”, añade Nuria Izquierdo-Useros, investigadora principal en IrsiCaixa y co-líder del estudio. Por su parte, el personal investigador celebra que con poca concentración de plitidepsina se alcance un potente efecto antiviral.

Un tratamiento para combatir distintas variantes

Por lo general, los virus disponen de pocas dianas terapéuticas a las que se pueden dirigir los fármacos. Además, debido a su capacidad para mutar, estas dianas pueden dejar de ser efectivas. Por ello, encontrar puntos del ciclo de replicación viral altamente conservados puede resultar muy útil a la hora de diseñar fármacos antivirales de amplio espectro. “Una de las ventajas de plitidepsina respecto a otros antivirales es que, en lugar de actuar sobre el virus directamente, bloquea una molécula propia de las células, esencial para la replicación del SARS-CoV-2. Por eso es un gran candidato para combatir otras variantes del SARS-CoV-2 que puedan emerger”, concluyen Cristina Risco y Nuria Izquierdo-Useros.

CSIC Comunicación

 

Referencia científica:
Martin Sachse, Raquel Tenorio, Isabel Fernández de Castro, Jordana Muñoz-Basagoiti, Daniel Perez-Zsolt, Dàlia Raïch-Regué, Jordi Rodon, Alejandro Losada, Pablo Avilés, Carmen Cuevas, Roger Paredes, Joaquim Segalés, Bonaventura Clotet, Júlia Vergara-Alert, Nuria Izquierdo-Useros, Cristina Risco. Unraveling the antiviral activity of plitidepsin by subcellular and morphological analysis. Biorxiv (Preprint). DOI: https://doi.org/10.1101/2021.12.16.472880


 
 

 

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